Prediction of Properties from Simulations: Free Energies of Solvation in Hexadecane, Octanol, and Water

Monte Carlo (MC) statistical mechanics simulations have been carried out for more than 200 organic solutes, including 125 drugs and related heterocycles, in aqueous solution. The calculations were highly automated and used the OPLS-AA force field augmented with CM1P partial charges. Configurationally averaged results were obtained for a variety of physically significant quantities including the solute−water Coulomb and Lennard-Jones interaction energies, solvent-accessible surface area (SASA), and numbers of donor and acceptor hydrogen bonds. Correlations were then obtained between these descriptors and gas to liquid free energies of solvation in hexadecane, octanol, and water and octanol/water partition coefficients. Linear regressions with three or four descriptors yielded fits with correlation coefficients, r2, of 0.9 in all cases. The regression equation for log P(octanol/water) only needs four descriptors to provide an rms error of 0.55 for 200 diverse compounds, which is competitive with the best fr...